Exploiting the 7-methylimidazo[1,5-a]pyrazin-8(7H)-one scaffold for the development of novel chemical inhibitors for Bromodomain and Extraterminal Domain (BET) family

Yifei Yang; Pan Chen; Leilei Zhao; Fangqing Zhang; Bing Zhang; Changliang Xu; Huibin Zhang; Jinpei Zhou

doi:10.1016/j.bioorg.2019.103044

Exploiting the 7-methylimidazo[1,5-a]pyrazin-8(7H)-one scaffold for the development of novel chemical inhibitors for Bromodomain and Extraterminal Domain (BET) family

Bioorg Chem. 2019 Sep:90:103044. doi: 10.1016/j.bioorg.2019.103044. Epub 2019 Jun 11.

Authors

Yifei Yang¹, Pan Chen¹, Leilei Zhao², Fangqing Zhang², Bing Zhang², Changliang Xu³, Huibin Zhang⁴, Jinpei Zhou⁵

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
² Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
³ Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, PR China. Electronic address: cl.xu81@gmail.com.
⁴ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zhanghb80@163.com.
⁵ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.

PMID: 31220668
DOI: 10.1016/j.bioorg.2019.103044

Abstract

The bromodomain and extraterminal (BET) family of proteins play a crucial role in promoting gene expression of critical oncogenes. Novel BET bromodomain inhibitors with excellent potency, drug metabolism and pharmacokinetics (DMPK) properties were in strong need for development. We reported a series of potential BET inhibitors through incorporation of imidazole into pyridine scaffold. Among them, a novel BET inhibitor with 7-methylimidazo[1,5-a]pyrazin-8(7H)-one core, compound 28, was considered to be the most promising for in-depth study. Compound 28 exhibited excellent BRD4-inhibitory activity with IC₅₀ value of 33 nM and anti-proliferation potency with IC₅₀ value of 110 nM in HL-60 (human promyelocytic leukemia) cancer cell lines. Western Blot indicated that compound 28 can effectively trigger apoptosis in BxPc3 cells by modulating the intrinsic apoptotic pathway. In conclusion, these results suggested that compound 28 has merely potential for leukemia treatment.

Keywords: Anticancer; BET family; BRD4 inhibitors; Molecular docking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Drug Screening Assays, Antitumor
Humans
Imidazoles / chemical synthesis
Imidazoles / metabolism
Imidazoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Protein Binding
Protein Domains / drug effects*
Pyrazines / chemical synthesis
Pyrazines / metabolism
Pyrazines / pharmacology*
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors*
Transcription Factors / metabolism

Substances

Antineoplastic Agents
BRD4 protein, human
Cell Cycle Proteins
Imidazoles
Pyrazines
Transcription Factors